Controlled release combination of carbidopa/levodopa

ABSTRACT

A matrix or monolithic drug delivery system for the controlled release of carbidopa and levodopa consists of the two drugs uniformly dispersed in a polymer vehicle at a concentration that is greater than the solubility of either drug in the polymer. Treatment of parkinsonism with the controlled release formulation provides several advantages over treatment with the standard carbidopa/levidopa combinations presently employed.

BACKGROUND OF THE INVENTION

This is a division of application Ser. No. 223,861 filed July 25, 1988,now U.S. Pat. No. 4,832,957, which is a continuation-in-part ofcopending application Ser. No. 131,061, filed Dec. 11, 1987, abandoned,which in turn is a continuation-in-part of copending application Ser,No. 874,988, filed June 16, 1986, abandoned.

This invention is concerned with a controlled release formulation forthe simultaneous delivery of levodopa and carbidopa in the treatment ofparkinsonism whereby the adverse reactions and inadequacies oftenexperienced with the administration of standard carbidopa/levodopacombinations are minimized.

SINEMET® (Merck & Co., Inc., Rahway, N.J.) is the registered trademarkfor a therapeutic agent useful in the treatment of idiopathicParkinsonism. It is a combination of levodopa and carbidopa and isprovided in tablets of 10 mg carbidopa/100 mg of levodopa; 25 mg ofcarbidopa/250 mg of levodopa; and 25 mg of carbidopa/100 mg of levodopa.The usual dose is 3 to 4 tablets daily.

Before SINEMET was introduced to the market in 1975, parkinsonism wastreated with levodopa by itself. Large doses of levodopa were necessaryto adequately control the Parkinson syndrome and severe adversereactions, especially emesis, were experienced. To minimize theseadverse reactions attempts were made to delivery levodopa in a sustainedrelease fashion. In fact there was a product called Brocadopa Temtabs.Several studies failed to show any advantage of the sustained releaseformulation over a standard preparation. See Eckstein et al., TheLancet, Feb. 24, 1973, page 431 which states at 432, "for the majorityof parkinsonians in our study sustained-release levodopa offered nodefinite advantage over a standard preparation". Also curzon et al., TheLancet, Apr. 7, 1973, page 781, states, "These results suggest there isno practical advantage to be gained by the use of an oralsustained-release preparation of levodopa".

Therapy with SINEMET is widely accepted as the cornerstone in treatingidiopathic Parkinson's disease. However, "wearing-off" and "on-off"phenomena have emerged as major problems in the long-term treatment ofParkinson's disease. After two to three years, many patients begin toexperience oscillating motor fluctuations which become increasinglydisabling. The essential feature is a change from mobility toimmobility, which may occur many times a day. Predictable warning oftherapeutic effects, following each dose of SINEMET, is known as"wearing-off" and may first occur during stage II-III of the disease.Such response fluctuations occur in 15 to 40% of patients after two tothree years of treatment, and in a greater percentage with longerduration of illness. The fluctuations in levodopa levels which accompanySINEMET treatment may in themselves contribute to the development ofclinical oscillations.

The clinical manifestations of "on-off" include rapid and unpredictableswings from mobility to immobility. "On" periods can usually becorrelated with high or rising plasma levodopa levels and are oftenassociated with distinct, abnormal involuntary movements (dose-relateddyskinesias), while "off" periods are commonly but not invariablyassociated with low or falling plasma-levodopa levels. The relation of"off" periods to low plasma levodopa levels and the observation that theadministration of apomorphine during an "off" period may restorefunction suggests that most such periods are due to cerebral dopaminedeficiency. Frequent dosage administration helps to alleviateoscillating clinical responses but dyskinesias and bradykinetic episodesmay still occur.

Intravenous levodopa has been used to provide stable plasma levels of2000 to 5000 ng/ml in advanced parkinsonian patients. This procedurereduces motor oscillations, but optimal response in some patients stillinclude either tremor and bradykinesia or mobility with dyskinesia. Highprotein meals cause a decline in response without affecting plasmalevodopa levels, presumably by inhibiting transport of levodopa into thebrain.

The above considerations indicate that a dosage preparation of SINEMETpossessing less rapid dissolution properties and providing a more evenplasma level profile of levodopa should be efficacious in alleviatingsome but not all oscillating therapeutic responses.

If the development of clinical fluctuations is promoted by oscillatinglevodopa levels, a controlled release preparation may also help toprevent the emergence of "wearing-off" and "on-off" phenomena.

Now, with the present invention there is provide a controlled releaseform of the combination of carbidopa/levodopa designed to obviate or atleast alleviate problems associated with the standard combinationtherapy. Dyskinesias and other central nervous system side effects, andgastrointestinal side effects may be reduced in patients sensitive tohigh plasma levodopa levels. Patients with oscillating symptoms shouldrespond to the more constant plasma levodopa levels with a more evenclinical response. Furthermore, controlled release SINEMET is expectedto represent a more convenient dosage form (i.e., allowing for lessfrequent medication) for many patients who require standard SINEMET fouror more time a day. A twice-daily dosage regimen may also be feasible insome patients.

DETAILED DESCRIPTION OF THE INVENTION

The novel controlled release tablet of carbidopa/levodopa of thisinvention is a matrix or monolithic drug delivery system containingcarbidopa and levodopa as active ingredients. The system consists of thetwo drugs, uniformly dispersed in a polymer vehicle at a concentrationthat is greater than either drug solubility in the polymer vehicle whichis either a single or a combination of polymers.

The novel delivery system provides slow release of both drug componentseither by erosion or by a diffusion controlled mechanism, depending onthe particular polymer vehicle.

Release of drug by erosion occurs by slow disintegration of the tabletsurface. Release of drug by diffusion occurs either through the spacebetween the macromolecular polymer chains or through a porous networkfilled with aqueous medium. Optimum erosion or diffusion conditions canbe achieved by controlling the crystalline phase porous structure,degree of swelling, polymer type, polymer ratio, drug concentration andother salient parameters.

FIG. 1, is a cross-section of a tablet-shaped homogeneous polymer matrixshowing the drug components, 1, homogeneously dispersed in the matrix.

FIG. 2, is a schematic representation of the same polymer matrix, 1,after some of the drug has been delivered by diffusion by entry ofliquids into the tortuous microporous channels, 2, followed by exit ofdrug solution through the same tortuous path. This matrix remainsessentially intact while delivering its drug content.

FIG. 3, is a cross-section of a schematic representation of the polymermatrix, 1, after some of the drug has been delivered by erosion byliquids whereby polymer, 1, and active ingredients, 2, are dispersed inthe fluid as solute or suspensoid.

FIG. 3a, is a schematic representation of the polymer matrix, 1, afteressentially all of the drug, 2, has been delivered by erosion. Thismatrix completely disintegrates while delivering its drug content.

The polymer vehicle is a mono-polymer or co-polymer or combinationsthereof and are selected from: water soluble polymers such ashydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, starch, methyl cellulose; and lesswater-soluble polymers such as polyvinyl acetate-crotonic acidcopolymer, polyvinyl chloride, polyethylene, cellulose acetate,polyvinyl alcohol, ethylene vinyl acetate copolymer, polyvinyl acetate,polymethyl methacrylate, ethyl cellulose and the like. The preferredvehicle is a combination of the water soluble polymer, hydroxypropylcellulse and the less water soluble co-polymer of polyvinylacetate-crotonic acid.

Other components of the novel formulation are optional dyes and tabletlubricants such as: metallic salts of acids including aluminum stearate,calcium stearate, magnesium stearate, sodium stearate, and zincstearate; fatty acids, hydrocarbons and fatty alcohols including stearicacid, palmitic acid, liquid paraffin, stearyl alcohol, and palmitylalcohol; fatty acid esters including glyceryl monostearate, glyceryl(mono- and di-) stearate, triglycerides, glyceryl (palmiticstearic)ester, sorbitan monostearate, saccharose monostearate, saccharosemonopalmitate, and sodium stearyl fumarate; alkyl sulfates, includingsodium lauryl sulfate, and magnesium lauryl sulfate; polymers includingpolyethylene glycols, polyoxyethylene glycols, andpolytetrafluoroethylene (Teflon); and inorganic materials such as talc.The preferred tablet lubricant is magnesium stearate.

In a typical formulation the components thereof are present in thefollowing quantities:

    ______________________________________                                                   Quantity                                                           Component    Range         Preferred Range                                    ______________________________________                                        Levodopa     20-1200   mg.sup.(1)                                                                            100-400 mg                                     Carbidopa    5-300     mg.sup.(1)                                                                            25-100  mg                                     Water Soluble                                                                 Polymer      0-120     mg.sup.(2)                                                                            5-25    mg                                     less water soluble                                                            polymer      0-120     mg.sup.(2)                                                                            2-50    mg                                     lubricant    0-25      mg      1-10    mg                                     ______________________________________                                         .sup.(1) The relative amounts of carbidopa to levodopa are preferably fro     about 1 carbidopa/10 levodopa to 1 carbidopa/4 levodopa.                      .sup.(2) In a given formulation both polymers cannot be 0 mg.            

A process for preparing the novel formulations comprises mixinglevodopa, carbidopa and colorants with a hydroalcoholic or othersuitable solvent dispersion of the polymer(s), drying, milling, mixingwith the lubricant and compressing into tablets.

Alternatively the formulation can be prepared by mixing levodopa,carbidopa and colorants and adding hydroxyproyplcellulose and/orpolyvinyl acetate/crotonic acid copolymer, either dry or dispersed in asolvent such as water, alcohol or hydroalcohol. The mixture is dried,mixed with lubricant and compressed into tablets.

Specific examples of the novel controlled release formulation of thisinvention are as follows:

EXAMPLE 1

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         200 mg                                                   Carbidopa Hydrous USP                                                                              54 mg                                                    Cellulose Acetate    50 mg                                                    Magnesium Stearate Impalpable                                                                      5.5 mg                                                   Powder NF                                                                     FD & C Blue No. 1    1.0 mg                                                   ______________________________________                                    

EXAMPLE 2

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         200 mg                                                   Carbidopa Hydrous USP                                                                              54 mg                                                    Vinyl Acetate/Crotonic Acid                                                                        6.5 mg                                                   Copolymer.sup.(1)                                                             Hydroxypropyl Cellulose NF.sup.(2)                                                                 17.0 mg                                                  Magnesium Stearate Impalpable                                                                      3.0 mg                                                   Powder NF                                                                     Red 347 Mapico       0.4 mg                                                   Yellow D & C No. 10 Aluminum                                                                       1.0 mg                                                   Lake HT                                                                       ______________________________________                                         .sup.(1) Vinac ASB516 ® containing about 5% crotonic acid; molar          viscosity 15-17 cps; molecular weight 95,000; available from Air Products     and Chemicals, Inc., Box 538, Allentown, PA 18105, U.S.A.                     .sup.(2) Klucel LF ®, molecular weight, 75,000; viscosity of 5%           aqueous solution 75-150 cps; available from Hercules, Incorporated,           Wilmington, Delaware, 19894, U.S.A.                                      

EXAMPLE 3

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         200 mg                                                   Carbidopa Hydrous USP                                                                              54 mg                                                    Carboxyvinyl Polymer 60 mg                                                    Microcrystalline Cellulose                                                                         20 mg                                                    Magnesium Stearate Impalpable                                                                      5.5 mg                                                   Powder NF                                                                     FD & C Red No. 3     1.0 mg                                                   ______________________________________                                    

EXAMPLE 4

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         200 mg   100 mg.                                         Carbidopa Hydrous USP                                                                              54 mg    27 mg.                                          Vinyl Acetate/Crotonic Acid                                                                        5.0 mg   2.5 mg                                          Copolymer.sup.(1)                                                             Hydroxypropyl Cellulose NF.sup.(2)                                                                 17.0 mg  8.5 mg                                          Magnesium Stearate Impalpable                                                                      3.0 mg   1.5 mg.                                         Powder NF                                                                     Red 347 Mapico       0.3 mg   0.15 mg.                                        Yellow D & C No. 10 Aluminum                                                                       1.1 mg   0.55                                            Lake HT                                                                       ______________________________________                                         .sup.(1) See footnote, Example 2.                                             .sup.(2) See footnote, Example 2.                                        

EXAMPLE 5

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         200 mg                                                   Carbidopa Hydrous USP                                                                              54 mg                                                    Hydroxypropyl Cellulose NF.sup.(1)                                                                 90 mg                                                    Magnesium Stearate Impalpable                                                                      8.0 mg                                                   Powder NF                                                                     Red 347 Mapico       0.4 mg                                                   Yellow D & C No. 10 Aluminum                                                                       1.0 mg                                                   Lake HT                                                                       ______________________________________                                         .sup.(1) See footnote (2), Example 2.                                    

EXAMPLE 6

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         400 mg                                                   Carbidopa Hydrous USP                                                                              108 mg                                                   Polymethyl Methacrylate                                                                            120.0 mg                                                 Magnesium Stearate Impalpable                                                                      5.5 mg                                                   Powder NF                                                                     FD & C Red No. 3     0.4 mg                                                   Yellow D & C No. 10 Aluminum                                                                       1.0 mg                                                   Lake HT                                                                       ______________________________________                                    

EXAMPLE 7

    ______________________________________                                        Ingredient           Per Tablet                                               ______________________________________                                        Levodopa USP         100 mg                                                   Carbidopa Hydrous USP                                                                              54 mg                                                    Ethyl Cellulose      20.0 mg                                                  Methyl Cellulose     5.0 mg                                                   Magnesium Stearate Impalpable                                                                      5.5 mg                                                   Powder NF                                                                     FD & C Red No. 3     0.4 mg                                                   Yellow D & C No. 10 Aluminum                                                                       1.0 mg                                                   Lake HT                                                                       ______________________________________                                    

Two controlled release formulations, No. 1 and No. 2 were compared tostandard SINEMET in 20 patients with uncomplicated Parkinson's disease.Means disability scores were similar over two weeks in patients whoreceived No. 1 or standard SINEMET and in patients who received No. 2 orstandard SINEMET. (Because of the design of this study, the group of 10patients which received No. 1 was different from the 10 patients whoreceived No. 2; however, all patients received standard SINEMET).

    ______________________________________                                                           Per Tablet (mg)                                            Ingredient           No. 1   No. 2                                            ______________________________________                                                             CR-2    CR-3                                             Levodopa             100     200                                              Carbidopa            50      50                                               Polyvinyl acetate-   3       20                                               Crotonic acid                                                                 Co-polymer.sup.(1)                                                            Magnesium Stearate   1.7     5.5                                              Hydroxypropyl Cellulose NF.sup.(2)                                                                 10      --                                               ______________________________________                                         .sup.(1) See footnote, Example 2.                                             .sup.(2) See footnote, Example 2.                                        

The pharmacokinetic profiles of the sustained release formulations wereclearly different from that of standard SINEMET. Patients on No. 1achieved peak plasma levodopa concentrations 2.8±1.2 hours after dosing,compared to a T_(max) of 1.1±0.33 hours with standard SINEMET. For theNo. 2 preparation, T_(max) was 3.1±2.2 hours, compared to 1.4±0.5 hourswith standard SINEMET. The eight hour bioavailabilities of No. 1 and No.2 relative to standard SINEMET were estimated to be 86% and 75%,respectively.

Although mean peak plasma levodopa concentrations for No. 1 and No. 2were only about half of those produced by SINEMET, and the 8 hour levelsfollowing No. 1 or No. 2 administration exceeded those with SINEMET,indicating sustained release properties for both CR formulations.

Based on these results, and the preferable 1:4 ratio of the No. 2tablet, four open-label clinical and pharmacokinetic studies of No. 2were conducted in parkinsonian patients with motor fluctuations. Among30 such patients (22 with "wearing off" and 8 with unpredictable"on/off"), only a few showed marked improvement with decreased "off"time and smooth response during the day. Many others benefited fromnighttime improvement including better sleep and mobility, and improvedearly morning function. Sustained elevated plasma levodopa levels wereachieved, but were associated with unpredictable variability.

The No. 2 formulation proved to be extremely difficult to use because ofa marked delay in onset of response after each dosage, a requirement forvery high daily dosages (150-400% of standard SINEMET), and very poorcorrelation between time of dose and rise in plasma levodopa levels. INfact, nighttime and early morning plasma levels were sometimes higherthan daytime levels, although dosing occurred throughout the day and notat night. Severe, sustained, and unpredictable periods of dyskinesiasand similarly sustained "off" periods were observed. B.I.D. dosageadministration was unsuccessful in 9 of 9 patients with mild to moderatefluctuations. Formulation No. 2 had to be given nearly as frequently asstandard SINEMET in most patients.

The results of these studies strongly indicated that the release rateand bioavailability of the No. 2 tablet were too low in vivo, andprobably very sensitive to effects of food and gastric pH. It appearedthat in many patients much of the daytime dosage was stored in thestomach and not released until nighttime. A fragmentable matrix withmore rapid dissolution characteristics, such as No. 1, had the potentialto eliminate some of these problems.

These considerations led to the development of the No. 3 formulation,(Example 4) which has the same in vitro dissolution properties andpolymeric matrix as No. 1 but contains 50 mg of carbidopa and 200 mg oflevodopa. Fifty patients were enrolled in the No. 3 studies, andpreliminary clinical and/or pharmacokinetic data are available fromapproximately 40 of them.

All four investigators consider the No. 3 formulation to be much easierto use than No. 2, due to 1) predictable onset of response, 2) dosagerequirements which are comparable to or slightly higher than standardSINEMET, and 3) more sustained therapeutic action during the day. Mostpatients who have completed the initial phase of the No. 3 trailsrequested long-term treatment because of clinical improvement. Ingeneral, dosing frequency can be reduced 25-50% with No. 3 relative tostandard SINEMET. Clinical fluctuations are reduced throughout the dayand occasionally eliminated. Patients with mold to moderate fluctuations(especially end-of-dose "wearing-off") benefit most, although half ofthe more severe patients have also improved. Pharmocokinetic dataindicate that plasma levodopa levels are sustained for 3-6 hoursfollowing a dose of No. 3, as compared to 1-2 hours with standardSINEMET.

Onset of response after a single dose of No. 3 is less than withstandard SINEMET and may require 45 minutes. In patients with advanceddisease, nighttime and early-morning response with No. 3 is better thanwith standard SINEMET but notably less than with No. 2. Plasma L-DOPAlevels correlate well with these observations in that early morningL-DOPA levels are moderately higher with No. 3 than standard SINEMET butmuch less than with No. 2.

Dyskinesia, mental confusion and psychosis have been observed at higherdoses in patients who had similar side effects with standard SINEMET.Sustained dyskinesias or "off" periods have not been significantproblems to date.

Another formulation (Example 2) with dissolution properties intermediateto those of No. 2 and No. 3 has also been developed. This formulationwill provide nighttime benefits in severe patients over those seen withNo. 3

What is claimed is:
 1. A controlled release oral dosage formulationcomprising a uniform dispersion of 25-100 mg of carbidopa and 100-400 mgof levodopa in a polymer vehicle comprising 5-25 mg of a water-solublehydroxypropylcellulose polymer and 2-50 mg of a less water-solublepolyvinylacetatecrotonic acid copolymer whereby, followingadministration, the carbidopa and levodopa are released slowly andsimultaneously from the formulation.
 2. The formulation of claim 1comprising 200 mg. of levodopa and 50 mg. of carbidopa or 100 mg. oflevodopa and 25 mg. of carbidopa.
 3. The formulation of claim 1comprising 200 mg of levodopa, 50 mg of carbidopa, 5-6.5 mg of vinylacetate-crotonic acid copolymer and about 17 mg of hydroxypropylcellulose.
 4. The formulation of claim 1 comprising 100 mg of levodopa,25 mg of carbidopa, 2.5 mg of vinylacetatecrontic acid copolymer andabout 8.5 mg of hydroxypropylcellulose.